Trinucleotide Repeat Disorders - Trinucleotide Repeat Expansion

Trinucleotide Repeat Expansion

Trinucleotide repeat expansion, also known as triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations.

Triplet expansion is caused by slippage during DNA replication. Due to the tandem repeats in the DNA sequence and the instability of the sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and the daughter strand being synthesized. In essence, a nick one side of the DNA strand is caused by cleavage by endonuclease whereby the repetitive triplet is extended and sealed by DNA polymerase and DNA ligase, respectively. If the loop out structure is formed from sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. In general, the larger the expansion the more likely they are to cause disease or increase the severity of disease. This property results in the characteristic of anticipation seen in trinucleotide repeat disorders. Anticipation describes the tendency of age of onset to decrease and severity of symptoms to increase through successive generations of an affected family due to the expansion of these repeats. In 2006, a model of expanding the triplets by involving RNA:DNA intermediate formed in repeat transcription or in post-transcription was proposed, and similar ideas turned to be an ongoing issue of mechanistic studies ever since.

In 2007, a new disease model was produced to explain the progression of Huntington's Disease and similar trinucleotide repeat disorders, which, in simulations, seems to accurately predict age of onset and the way the disease will progress in an individual, based on the number of repeats of a genetic mutation.